Dextromethorphan (DM, (+)-3-methoxy-17-methyl-9a,13a,14a-morphinan), a widely used over-the-counter antitussive agent, is a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor and is protective against the adverse effect of homocysteine (Hcy) and its metabolites. DM, the D-isomer of the opiate agonist levorphanol, has none of the analgesic or sedative effects associated with the opiates. DM, acting as an antagonist at NMDA receptors, suppresses the transmission of nerve impulses and nerve signals mediated through NMDA receptors. In addition, DM has also been reported to suppress activity at neuronal calcium channels.
Naloxone (trade name Narcan) is a drug used to counter the effects of overdosing on opiates such as heroin or morphine. Naloxone has been distributed as part of emergency kits to heroine addicts, which has been shown to reduce death rates. The drug also blocks the action of pain-lowering endorphins which the body produces naturally. The likely reason for this is that these endorphins operate on the same opiate receptors.
Macrophages secrete numerous other effectors including reactive oxygen species, eicosanoids, tumour necrosis factor alpha (TNF-α), interleukin-1 (IL-1) and interleukin-6 (IL-6). Macrophage-derived transforming growth factor beta promotes fibrosis. Existing cardiovascular treatments including angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, aspirin, cholesterol reduction agents especially statins may inhibit macrophages. The interaction of NO-donors with macrophages and apoptosis is complex and bifunctional. Traditional anti-inflammatory agents such as glucocorticoids and cyclophosphamide have very serious side effects and are probably inappropriate.
Atherosclerosis remains a leading cause of morbidity and mortality worldwide. Central to the pathogenesis of atherosclerosis is the infiltration of monocytes/macrophages in the arterial wall and the involvement of inflammation. Macrophages play a diverse array of roles in atherogenesis. They functions as a scavenger cell that takes up oxidized low-density lipoprotein (oxLDL) and become foam cells in the initial lesion of atherosclerosis. After activation, macrophages are capable of producing free radicals and pro-inflammatory factors, all of which are critical for the promotion of cellular proliferation and inflammation in atherosclerosis. Evidence indicates that atherosclerotic lesions could be decreased if monocyte/macrophage extravasation and activation is inhibited (Gosling J, et al., J Clin Invest, 103:773-8, 1999). Naloxone is a non-selective antagonist of the opioid receptors that are widely expressed not only in the central nervous system but also on the endothelium and monocytes. Previous animal studies found that naloxone can significantly decrease the inflammatory response in septic shock. It inhibits the production of tumor necrosis factor-α (TNF-α) induced by lipopolyssacharide (LPS) in mice. Recent studies also show that naloxone reduces the pro-inflammatory factors and superoxide generation from LPS-induced microglia, the resident macrophages within the nervous system (Liu B, Hong J S., J Pharmacol Exp Ther, 304:1-7, 2003).